Could neonatal testosterone replacement prevent alterations induced by prenatal stress in male rats? Oduvaldo Ca ˆmara Marques Pereira a, * , Maria Martha Bernardi b , Daniela Cristina Ceccatto Gerardin a,b a Department of Pharmacology, Institute of Biosciences, UNESP, Botucatu, Brazil b Department of Pharmacology, Institute of Biomedical Sciences, USP, Sao Paulo, Sao Paulo, Brazil Received 16 August 2005; accepted 31 October 2005 Abstract The present study was designed to examine whether testosterone replacement is able to prevent some effects of maternal restraint stress — during the period of brain sexual differentiation — on endocrine system and sexual behavior in male rat descendants. Pregnant rats were exposed to restraint stress for 1 h/day from gestational days 18 to 22. At birth, some male pups from these stressed rats received testosterone propionate. The neonatal testosterone replacement was able to prevent the reduction in anogenital distance at 22 days of age observed in pups from stressed pregnant rats as well as prevents the decrease in testosterone levels during the adulthood of these animals. Testosterone replacement in these males also presented an improvement in sexual performance. In this way, testosterone replacement probably through increasing neonatal level of this hormone was able to prevent the later alterations caused by the prenatal stress during the period of brain sexual differentiation. D 2005 Published by Elsevier Inc. Keywords: Prenatal stress; Brain sexual differentiation; Testosterone; Sexual behavior; Male rat Introduction Sexual differentiation of the hypothalamus of male and female rats involves complex phenomena and an important participation of estrogen, as well as androgens (Dohler, 1991). In male rats, testosterone surges markedly on days 18–19 of gestation (Weisz and Ward, 1980) and again during the first few hours following parturition (Baum et al., 1988; Corbier et al., 1978; Lalau et al., 1990; Slob et al., 1980). During this period of brain sexual differentiation, testosterone or its metabolites are fundamental for masculinization and defemi- nization of sexual behavior, for the establishment of gonado- tropin secretion patterns, and also for various morphological indices. In the absence of testosterone or its metabolites, sexually dimorphic structures and functions are feminized (Rhees et al., 1997). The stress response induced by physical or emotional challenges has been recognized as a profoundly disruptive factor in reproductive function in both males and females (Velazquez-Moctezuma et al., 1993; Wang et al., 1995; Retana- Marques et al., 1998; Rhees et al., 1999; Ward et al., 2002). The prenatal stress during the critical stage of hypothalamic differentiation is related to reduced fertility and fecundity (Anderson et al., 1986) and leads to altered sexual behavior (Ward, 1984) in male offspring through an increased cortico- sterone level. During stressful situations the activation of the hypothalamus – pituitary – adrenal axis was greater in prenatally stressed animals compared to non-stressed controls. Thus, prenatal stress partly affects adult behavior by altering the regulation of the hypothalamus – pituitary – adrenal axis (Szuran et al., 2000). Prenatal stress can alter masculine function even more directly by reducing plasma testosterone levels in adult males (Anderson et al., 1985; Pollard and Dyer, 1985). It has been hypothesized that prenatal stress disrupts the normal maternal hormonal milieu and suppresses the fetal testosterone peak on gestational days (GD) 18 and 19, a necessary peak for the later expression and maintenance of male sexual behavior 0024-3205/$ - see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.lfs.2005.10.035 * Corresponding author. Fax: +55 14 3815 3744. E-mail address: pereira@ibb.unesp.br (O.C.M. Pereira). Life Sciences 78 (2006) 2767 – 2771 www.elsevier.com/locate/lifescie